Benzo [g] quinoline derivatives for treating glaucoma and myopia

ABSTRACT

The invention provides a compound of formula I 
                 
 
wherein A, B, X, Y and R 1  are as defined in the description, and a process for preparing them. The compounds of formula I are useful as pharmaceuticals.

The present invention relates to novel benzo [g] quinoline derivatives,their preparation, their use as pharmaceuticals and pharmaceuticalcompositions containing them.

More particularly the present invention provides a compound of formula I

wherein

-   A and B are each H or form together an additional bond,-   X is CH₂ or CO,-   Y is O, S, NR₂ [R₂ being H or (C₁₋₄)alkyl], CH₂ or O—CH₂, and-   R₁ is H or (C₁₋₄)alkyl    in free base or acid addition salt form.

The above-defined alkyl groups preferably represent methyl.

When A and B are each H, the X—Y-pyrimidine substituent preferablypresents the configuration 3R.

X is preferably CH₂.

Y is preferably O or S, even more preferably S.

R₁ is preferably methyl, more preferably methyl in position 4 of theaddressed pyrimidine.

In a preferred embodiment A and B each represents H, X is CH₂, Yrepresents S and R₁ is methyl.

In a further aspect the invention provides a process for the productionof the compounds of formula I and their acid addition salts, whereby ina compound of formula II

wherein A, B, X, Y and R₁ are as defined above and R₃ is (C₁₋₄)alkyl,the alkoxy group is converted into a hydroxy group, and the compounds offormula I thus obtained are recovered in free base or acid addition saltform.

The reaction can be effected according to known methods, e.g. usinghydrobromide acid or boron tribromide. In formula II, R₃ is preferablymethyl.

Working up the reaction mixtures obtained according to the above processand purification of the compounds thus obtained may be carried out inaccordance to known procedures.

Acid addition salts may be produced from the free bases in known manner,and vice versa. Suitable acid addition salts for use in accordance withthe present invention include for example the hydrochloride.

The starting compounds of formula II wherein A and B are each H may beproduced from the corresponding compounds of formula III_(a)

wherein R₃ is as defined above, for example as described in Example 1.

The compounds of formula III_(a) are known or may be produced inanalogous manner to known procedures.

The starting compounds of formula II wherein A and B together form anadditional bond may be produced from the corresponding compounds offormula III_(b)

wherein R₃ is as defined above.

The compounds of formula III_(b) are known or may be produced inanalogous manner to known procedures.

The compounds of formula I and their physiologically acceptable acidaddition salts, referred to hereinafter as agents of the invention,exhibit valuable pharmacological properties in animal tests and aretherefore useful as pharmaceuticals.

In particular, the agents according to the invention effect a decreaseon the intraocular pressure in rabbits, at concentrations of e.g. 10 to100 μM. Male rabbits of ca. 2.5 kg are fixed in cages leaving theirheads free. The solutions with the compound to be tested are applied tothe right eye and the placebo solutions to the left eye (2 drops each,i.e. ca. 40 μl). The eyes are firstly anaesthetized with a solutioncontaining Novesine (0.4%) and Fluorescein (0.05%) and the ocularpressure is determined at various intervals after administration (10,20, 30, 60, 90, 120, 180 and 240 minutes), whereby an applanationtonometer according to Goldberg is used.

The agents of the present invention, in particular the preferred agents,exhibit a surprising strong efficacy in lowering the intraocularpressure (IOP) and an excellent duration of action. Moreover, theyexhibit an excellent tolerability.

The agents according to the invention are therefore in particular usefulin the treatment of glaucoma and myopia. A more preferred use isglaucoma treatment, lowering of IOP.

For the above mentioned indication, the appropriate dosage will ofcourse vary depending upon, for example, the compound employed, thehost, the mode of administration and the severity of the condition beingtreated. However, in general, satisfactory results in animals areindicated to be obtained at a daily dosage of from about 0.1 to about 10mg/kg animal body weight. In larger mammals, for example humans, anindicated daily dosage is in the range from about 5 to about 200 mg,preferably about 10 to about 100 mg of the compound convenientlyadministered in divided doses up to 4 times a day or in sustainedrelease form.

The agents of the invention may be administered in free form or inpharmaceutically acceptable salt form. Such salts may be prepared inconventional manner and exhibit the same order of activity as the freecompounds.

Accordingly the present invention provides an agent of the invention foruse as a pharmaceutical, e.g. in the treatment of glaucoma and myopia.

The present invention furthermore provides a pharmaceutical compositioncomprising an agent of the invention in association with at least onepharmaceutically acceptable diluent or carrier. Such compositions may beformulated in conventional manner. Unit dosage forms contain, forexample, from about 0.25 to about 50 mg of an agent according to theinvention.

Agents according to the invention may be administered by anyconventional route, for example parenterally e.g. in form of injectablesolutions or suspensions, or enterally, preferably orally, e.g. in theform of tablets or capsules.

More preferably, they are applied topically to the eye in about 0.0001to 2%, preferably in about 0.001 to 0.5%, and more preferably in about0.01 to 0.1% ophthalmological solutions.

The ophthalmic vehicle is such that the compound is maintained incontact with the ocular surface for a sufficient time period to allowthe compound to penetrate the corneal and internal regions of the eye.

The pharmaceutically acceptable ophthalmic vehicle may be e.g. anointment, vegetable oil, or an encapsulating material.

In accordance with the foregoing, the present invention also provides anagent of the invention for use as a pharmaceutical in the treatment ofglaucoma and myopia.

Moreover the present invention provides the use of an agent of theinvention, for the manufacture of a medicament for the treatment ofglaucoma and myopia.

In still a further aspect the present invention provides a method forthe treatment of glaucoma and myopia in a subject in need of suchtreatment, which comprises administering to such subject atherapeutically effective amount of an agent of the invention.

The present invention relates also to any compound disclosed in theworking examples. It further relates to any independent and/or dependantclaims disclosed infra.

The following examples illustrate the invention. The temperatures aregiven in degrees Celsius and are uncorrected.

EXAMPLE 1[3R,4aR,10aR]-1-methyl-3β-{4-methyl-1,3-pyrimidin-2yl}thiomethyl-6-hydroxy-1,2,3,4,4aα,5,10,10aβ-octahydrobenzo[g]quinoline

a) [3R,4aR,10aR]-1-methyl-3β-hydroxymethyl-6-methoxy-1,2,3,4,4aα,5,10,10aβ-octahydrobenzo[g]quinoline

To a solution of 5.78 g (20 mM)[3R,4aR,10aR]-1-methyl-3β-methoxycarbonyl-6-methoxy-1,2,3,4,4aα,5,10,10aβ-octahydrobenzo[g]quinolinein 100 ml toluene, a solution of 12 ml SDBA (70% in toluene, 42 mM) isadded in drops under argon at room temperature within one hour. Then 10ml NaOH (30%) are added in drops to the ice cooled reaction mixture. Theprecipitated crystals are filtered off, washed with water and tolueneand dried. The resulting title compound has a m.p. of 148°; [α]²⁰_(D)=−120° (c=0.425 in ethanol).

b)[3R,4aR,10aR]-1-methyl-3β-mesyloxymethyl-6-methoxy-1,2,3,4,4aα,5,10,10aβ-octahydrobenzo[g]quinoline

12 ml (153 mM) methanesulfochloride are added in drops to a solution of20 g (76.5 mM) of the compound obtained under a) in 150 ml pyridine atroom temperature. The temperature is kept below 45° by ice cooling.After stirring for 2 hours at room temperature, the solution is adjustedto pH 7-8 with saturated KHCO₃ solution at 0° and extracted withethylacetate. After drying over Na₂SO₄, filtering and concentrating byevaporation, the title compound is obtained as beige crystals anddirectly used for the next step.

c)[3R,4aR,10aR]-1-methyl-3β-{4-methyl-1,3-pyrimidin-2yl}thiomethyl-6-methoxy-1,2,3,4,4aα,5,10,10aβ-octahydrobenzo[g]quinoline

A solution of 6 g (17.7 mM) of the compound obtained under b) and 3.4 g(27 mM) 2-mercapto-4-methyl-1,3-pyrimidin in 60 ml dimethylformamide ismixed with 6 ml 2N NaOH and stirred at 65° for 18 hours. The so obtainedsuspension is concentrated by evaporation. The crude productcrystallises. The suspension is cooled to 5-10°, washed withethylacetate and dried. Chromatography on silicagel with ethylacetatecontaining 10% ethanol and 0.01% NH₃ yields the title compound as beigecrystals.

d)[3R,4aR,10aR]-1-methyl-3β-{4-methyl-1,3-pyrimidin-2yl}thiomethyl-6-hydroxy-1,2,3,4,4aα,5,10,10aβ-octahydrobenzo[g]quinoline

To a solution of 4.06 g (11 mM) of the product obtained under c) in 250ml methylenechloride, 40 ml of boron tribromide (1 M inmethylenechloride) are slowly added in drops at a temperature of −40°.The suspension is stirred for 2 hours at room temperature, neutralizedwith NH₃ and extracted with a mixture of 150 ml methylenechloride and100 ml isopropanol. After drying over Na₂SO₄, filtering andconcentration by evaporation, the title compound crystallises. Thecorresponding hydrochloride crystallises from methanol/ethanol 1:1during evaporation. M.p. 254°; [α]²⁰ _(D)=−90° (c=0.540 in ethanol/water1:1). C₂₀H₂₅N₃OS (HCl), MW=391.97.

1. A compound of formula I

wherein A and B are each H or form together an additional bond, X is CH₂or CO, Y is O, S, NR₂ [R₂ being H or (C₁₋₄)alkyl], CH₂ or O—CH₂, and R₁is H or (C₁₋₄)alkyl in free base or acid addition salt form.
 2. Thecompound of formula I, wherein A and B are each H, X is CH₂, Y is S andR₁ is methyl.
 3. A process for the preparation of a compound of formulaI as defined in claim 1, or a salt thereof, which includes the step ofconverting, in a compound of formula II

wherein A and B are each H or form together an additional bond, X is CH₂or CO, Y is O, S, NR₂ [R₂ being H or (C₁₋₄)alkyl], CH₂ or O—CH₂, and R₁is H or (C₁₋₄)alkyl, and R₃ is (C¹⁻⁴)alkyl, the alkoxy group into ahydroxyl group to form the compound of formula I, and recovering thecompound of formula I in free base or acid addition salt form.
 4. Apharmaceutical composition comprising a compound of claim 1 in free baseor pharmaceutically acceptable acid addition salt form, in associationwith a pharmaceutical carrier or diluent.
 5. A method for the treatmentof glaucoma and myopia in a subject in need of the treatment, whichcomprises administering to such subject a therapeutically effectiveamount of a compound of claim 1 in free base or pharmaceuticallyacceptable acid addition salt form.